Management of Toxicities of the New Oncologic Agents

Transcription

1 Management of Toxicities of the New Oncologic Agents Kevin P. Hubbard, DO, HMDC, MACOI Professor and Chair - Department of Specialty Medicine Kansas City University - College of Osteopathic Medicine

2 Financial Disclosures I have no real or apparent conflict of interest with the information presented in this lecture

3 Objectives Recognize the new oncologic agents used in the treatment of cancer Identify common side effects and toxicities related to the newer oncologic agents Develop management strategies to address these side effects and toxicities in the hospitalized oncology patient

4 Monoclonal Antibodies Agent Target Indications Toxicities Rituximab Ofatumumab Obinituzumab CD20 B-cell lymphomas and leukemias CRS Immunodeficiency Trastuzumab HER2 Breast cancer Cardiac disease Cetuximab EGFR Colorectal cancer Bevacizumab VEGF Colorectal cancer Breast cancer Renal cell cancer NSCLC Ramucirumab VEGFR Gastric cancer Diarrhea Exanthema Hypertension GI bleeding or perforation Thromboembolism

5 Tyrosine Kinase Inhibitors Agent Target Indications Toxicities Imatinib Dasatinib BCR-ABL CML ALL Pleural/pericardial effusion Pulmonary Hypertension Ponatinub Thromboembolism Erlotinib EGFR NSCLC Pancreatic cancer Exanthema, diarrhea GI bleeding or perforation Idelalisib PI3K B-cell lymphoma Trametinib MEK Melanoma Pneumonitis Colitis, hepatosis Diarrhea, edema Decreased LVEF

6 Tyrosine Kinase Inhibitors Agent Target Indications Toxicities Afliberecept VEGF Colorectal cancer Axinitinb VEGFR Renal cell cancer Hypertension GI bleeding or perforation Thromboembolism PRES Sorafenib Renal cell carcinoma Hepatocellular carcinoma Sunitinib Multiple kinases GIST Renal cell carcinoma Decreased LVEF Hypertension Pazopanib Soft tissue sarcoma Renal cell carcinoma

7 Bispecific Antibodies Agent Target Indications Toxicities Blinatumomab CD3/CD19 ALL B-cell lymphomas CRS Neurotoxicity (seizures) Transaminitis

8 Checkpoint Inhibitors Agent Target Indications Toxicities Ipilumumab CTLA-4 Melanoma Nivolumab Pembrolizumab Atezolizumab PD-1 PD-L1 Melanoma NSCLC Renal cell cancer Hodgkin s lymphoma Urothelial cancer NSCLC Immune-related adverse events: Diarrhea, colitis Hypophysitis Immunohepatitis Polyarthritis Neurological Avelumab Merkel cell cancer

9 Cellular Treatments Agent Target Indications Toxicities CAR T cells CD-19 ALL B-cell lymphomas CRS Neurotoxicity (seizures, encephalopathy, ischemia)

10 Cytokine Release Syndrome (CRS) Potentially life-threatening systemic inflammatory reaction seen after infusion of agents that target immune effector sites Events usually occur during or after first exposure to a new agent Driven by an increase of inflammatory cytokines which are released after the activation and cytotoxic damage of monocytes, macrophages, and different lymphocyte populations High levels of interleukin (IL)-6 have a central role

11 Cytokine Release Syndrome (CRS) Main Symptoms of Cytokine-Release Syndrome Constitutional Organ related Fever, chills, headache, asthenia, myalgia, arthralgia, back or abdominal pain Oliguria, bronchospasm, dyspnea, hypotension, tachycardia, arrhythmia, confusion, erythema, urticarial reaction, pruritus Lab tests Hypokalemia, BUN, GFR, abnormal blood counts and/or coagulation tests, CRP and/or procalcitonin

12 Cytokine Release Syndrome (CRS) Management The majority of events after the administration of monoclonal antibodies can be managed by antipyretics, antihistamines, corticosteroids, adequate fluid load, cardiopulmonary monitoring, and oxygen supplementation Rarely patients need to be admitted to the ICU for vasopressor support or hemofiltration

13 Cytokine Release Syndrome (CRS) CAR T cell therapy Grade 3 fever, hypotension, or hypoxia was reported in up to 80%, 40%, and 15% of treated patients, respectively in a recent study of toxicities (Brudno JN, Kochenderfer JN.. Blood. 2016;127(26): ) May affect the kidneys, liver, central nervous system (CNS), GI, and musculoskeletal system Monoclonal antibodies against IL-6 receptors (tocilizumab) Due to its high cost, as well as potential severe adverse events, including infections, reactivation of viruses, or tuberculosis and hepatotoxicity, treatment using tocilizumab should be limited strictly to critically ill patients

14 Central Nervous System Events Can occur with BABs and CAR T cells May happen at any time during CRS or as a singular complication May potentially necessitate intubation and mechanical ventilation for airway protection, as well as antiepileptic therapy in patients with seizures

15 Central Nervous System Events >50% who received blinatumomab in a phase 2 trial for acute B- lymphoblastic leukemia experienced neurologic events such as tremor, encephalopathy, cerebellar alteration, or seizures (Topp MS, et al. Lancet Oncol. 2015;16(1):57 66) 13% classified as severe or life-threatening Grade 3 neurotoxicity was reported in 13 of 27 patients in an early clinical trial with acute lymphoblastic leukemia patients undergoing CAR T-cell therapy (Turtle CJ, et al. Blood. 2015;126:3773) The pathophysiology of these neurotoxic effects is still unclear but, as in CRS, inflammatory cytokines seem to be involved

16 Central Nervous System Events Differential Diagnosis Encephalitis due to herpes virus species Focal infections such as toxoplasmosis Primary CNS hemorrhage due to altered coagulation cascade Clotting in CNS vasculature due to thrombophilia and secondary hemorrhage

17 Central Nervous System Events Management Dexamethasone Problem: steroids interfere with immune effects of treatment and may have a negative impact on tumor response! Anticonvulsants if seizures, prophylactic in patients who may be at increased risk

18 Immune-Related Adverse Events (IRAEs) Affected agents Checkpoint inhibitors (CTLA-4, PD-1/PD-L1, PD-2/PD-L2) Work by inhibiting the inhibitory signals sent from the cancer to T-cells Problem: agents can attenuate tolerance and cause overwhelming inflammation, tissue damage, and autoimmunity 85% (ipilumumab), 70% (PD-1/PD-L1)

19 Immune-Related Adverse Events (IRAEs) Main target tissues GI tract - most symptoms start 6 or more weeks after initiation of treatment Diarrhea Enterocolitis Perforation (rare) May require ICU admission

20 Immune-Related Adverse Events (IRAEs) Main target tissues Liver - not usually seen prior to 6 weeks after start of therapy Transaminitis Jaundice Etiology unclear, however cyclosporine has been reported to be effective in reversing severe liver toxicity (Huffman, BM, et al. Am J Clin Oncol Jul 26. doi: /COC )

21 Immune-Related Adverse Events (IRAEs) Main target tissues Skin - seen in more than 1/3 of all patients; usually self-limiting and manageable with conventional agents (Sibaud V, Am J Clin Dermatol Dec 18.) Maculopapular rash (eczema-like spongiotic dermatitis) Pruritis Vitiligo-like lesions Autoimmune skin disease (bullous pemphigoid, dermatomyositis, alopecia) Sarcoidosis

22 Immune-Related Adverse Events (IRAEs) Main target tissues Endocrine system - symptoms usually appear 9 or more weeks after initiation of treatment Hypophysitis Thyroiditis More common with ipilumumab than PD-1/PD-L1 agents

23 Interstitial Pneumonia and Pneumonitis Pneumocystis jirovecii and Cytomegalovirus are the main infectious agents for pneumonia in immunocompromised patients Risk Factors Lymphoproliferative malignancies Long-term use of glucocorticoids Lymphocytopenia (CD4 < 200/μL) Allogeneic hematopoietic stem cell transplantation

24 Interstitial Pneumonia and Pneumonitis Treatment of PJP (Maschmeyer G, et al., Journal of Antimicrobial Chemotherapy, Volume 71, Issue 9, 1 September 2016) High-dose cotrimoxazole ( mg/kg/day, intravenously over 14 days) is treatment of choice for first-line therapy An oral route from the beginning is an option only in stable patients with mild disease Pentamidine (4 mg/kg/d i.v.) or the combination of primaquine (30 mg/d) and clindamycin (600 mg/d x 3) can be considered in patients with contraindications to, or relapsing after, cotrimoxazole

25 Interstitial Pneumonia and Pneumonitis Drug-induced (non-infectious) pneumonitis Rituximab - 3-5%, mild Dasatinib (TKI) in about 28%; mild Idelalisib (PI3K-i) 10-20%; usually mild, but isolated severe pneumonitis and death have been reported Checkpoint inhibitors - 3-6%; mostly mild Steroids can help in moderate-severe cases; mild cases may be more limited and managed conservatively

26 Events Associated With Impaired Angiogenesis Arterial thromboembolism Bevacizumab 1% in breast cancer 11.3% in lung cancer

27 Events Associated With Impaired Angiogenesis Hypertension Bevacizumab Dasatinib (pulmonary) Cardiac ( LVEF, CHF) GI catastrophic events (hemorrhage, perforation) Bevacizumab (RR ) Bevacizumab Sorafenib Sunitinib

28 Other Toxicities Newer agents are less toxic than cytotoxic chemotherapy, but they are present nevertheless Usually present in normal tissues affected by the agents

29 Toxicities of the Newer Agents EGFR inhibitors - remember the E stands for epidermal, so skin toxicity is the major feature Maculopapular rash Resembles acne

30 Toxicities of the Newer Agents EGFR inhibitors Mild rash often associated with response to dose ( we re giving enough ) Starts 2-4 weeks after initiation of therapy, peaks at 2-4 months, then usually regresses over time

31 Toxicities of the Newer Agents BRAF inhibitors Squamous cell carcinomas and keratoacanthomas (19-26%) May develop within weeks of starting therapy Due to paradoxical activation of the mitogen activated protein kinase (MAP kinase) pathway that bypasses the inhibition of BRAF Surgical excision Does not require discontinuation of therapy

32 Toxicities of the Newer Agents BRAF inhibitors One reported case of rapid progression of CMML Other cutaneous toxicities (rash, photosensitivity reactions, alopecia) as with EGFR inhibitors QT prolongation (vemurafenib, due to CYP3A4 effects) Fever (dabrafenib, 28% of patients, may require discontinuation) Hyperglycemia (dabrafenib, 6% of patients, may require discontinuation)

33 Toxicities of the Newer Agents Monoclonal antibodies Fever, chills, back pain, wheezing Treated by premedication Reactivation of Hepatitis B virus and progressive multifocal leukoencephalopathy

34 Toxicities of the Newer Agents

35 Human Antibody Infusion Reactions Occurs with humanized antibody agents directed at targets on cancer cells Rituximab (Rituxan ) Trastuzumab (Herceptin ) Ofatumumab (Arzerra ) Bevacuzumab (Avastin ) Essentially any drug whose name ends in mab which means monoclonal antibody

36 Human Antibody Infusion Reactions Features Lab features Fever AST/ALT Chills Thrombocytopenia Nausea PT Wheezing Back pain

37 Human Antibody Infusion Reactions Management Premedicate: acetaminophen, diphenyhdramine, steroids (optional) If reaction occurs Stop infusion Administer (re-administer) above agents, re-start infusion at 50% initial infusion rate when symptoms resolve

38 Extravasation Spectrum of problems variable, from minor irritation to skin necrosis, ulceration, nerve damage, loss of limbs Most commonly occurs with agents known as vesicants Alkylating agents: mechlorethamine, cisplatin, mitomycin C DNA intercalating agents: doxorubicin, daunorubicin Plant alkaloids: vincristine, vinblastine, vinorelbine

39 Extravasation Management prevention is the goal! Monitor IV infusions carefully, patient/nurse should have low threshold for calling attention to symptoms of pain or swelling at the infusion site, redness Place PICC line or CVC in those patients who will receive high risk agents

40 Extravasation Management prevention is the goal! Immediately stop any infusion in question Apply cold compresses to area (warm compress with plant alkaloids) Topical DMSO 50% solution 1.5 ml q 6º x 7-14 days can relieve extravasations from mitomycin C and the anthracyclines

41 Extravasation Management prevention is the goal! Hyaluronidase 150 U in 1-3cc saline injected around site can alleviate extravasations from plant alkaloids and etoposide Sodium thiosulfate 0.17-mmo/L solution can be injected into mechlorethamine extravasations, may also be effective in cisplatin, carboplatin, cyclophosphamide, dacarbazine, and oxaliplatin If local measures fail, plastic surgeon consultation initiated

42 Extravasation Management prevention is the goal! Recall reaction: reappearance of ulcers or burns in areas previously extravasated by the same chemotherapy Extravasation kit with necessary products should be available in all chemotherapy administration areas, along with a listing of antidotes for each agent